Info

" This table was abstracted from Makin, H. L. ed. (1975). "Biochemistry of Steroid Hormones." William Clowes & Sons, Ltd., London. ^ FP, follicular phase; Ov, ovulatory peak; LP, luteal phase; LP2, secondary rise in LP following fall from value at Ov.

" This table was abstracted from Makin, H. L. ed. (1975). "Biochemistry of Steroid Hormones." William Clowes & Sons, Ltd., London. ^ FP, follicular phase; Ov, ovulatory peak; LP, luteal phase; LP2, secondary rise in LP following fall from value at Ov.

radioactive steroids, it has been possible to devise techniques of "compartmental" analysis that allow calculation of the secretion rate of steroids, as well as of their rate of disappearance from the plasma.

The metabolic clearance rate (MCR) of a steroid is the rate at which it is irreversibly inactivated. It is defined as "the volume of plasma cleared per unit of time." The plasma concentration (C) of any steroid will be determined by the balance between the rate of secretion (SR) and the MCR:

-, _ SR nmol _ (nmol/hr) ~ MCR ' liter _ (liters/hr)'

Frequently, the MCR for steroids approximates the plasma flow through the liver (1500 liters/day in humans).

The half-life of a hormone is defined as the time required to reduce the circulating plasma concentration of the steroid by one-half (in the absence of new secretion). There is a reciprocal relationship between half-life and MCR. As the MCR increases, the half-life is reduced, and as the MCR is reduced, the half-life increases. Since catabolism of a steroid hormone occurs on the "free" form of the steroid, the relatively high Kd of the plasma transport protein for a steroid will effectively reduce its ready accessibility for clearance and thereby increase its half-life.

Table 2-8 summarizes blood concentration, secretion rate, and metabolic clearance rate for a number of important steroid hormones. These data emphasize the complex interplay between biosynthesis and biodegradation, which permits an organism to regulate the blood concentrations of these potent hormonal

Principal

Steriod Starting Inactivation A:B Steriod structure representations conjugate class steroid steps ring junction of excreted product present"

Principal

Steriod Starting Inactivation A:B Steriod structure representations conjugate class steroid steps ring junction of excreted product present"

Vitamin D meta- 1,25(OH)iD3 1. Side chain cleavage between C-23 and — rrjOH

Vitamin D meta- 1,25(OH)iD3 1. Side chain cleavage between C-23 and — rrjOH

HO^ OH Calcitroic acid

"G, Glucuronide; S, sulfate.

FIGURE 2-35 Excretion pathways for steroid hormones.

APS (adenosine 5-phosphate) + pyrophosphate sulfurylase

[c] PAPS + steroid—OH -> steroid—O—S03~ + H~ + PAP [3', 5' phosphoadenosine]

FIGURE 2-36 Enzymatic steps involved with the production of "active" sulfate (PAPS).

agents. For a detailed consideration of this topic, the interested reader is referred to Tait and Horton (1966).

D. Inactivation of Steroid Hormones

Steroids are quite hydrophobic compounds, and many of the catabolic mechanisms not only inactivate the steroid hormone [i.e., markedly reduce its affinity for its receptor(s)] but also make the molecule more hydrophilic, thereby increasing its water solubility. The catabolic reactions occur mainly, although not exclusively, in the liver and are oxidative in nature. A significant increase in water solubility is effected by conjugation of the steroids with either sulfate or glucu-ronides; these steroid conjugates are excreted in large quantities in the urine.

Figure 2-35 summarizes some of the major excretory forms of these hormones for the six classes of steroids. The excreted species is a mixture of polyhydroxyl forms and the indicated glucuronide or sulfate. The sulfokinase enzymes have been shown to be present in the cytoplasm of the placenta, testes, adrenal cortex, and liver. These enzymes utilize "active sulfate" or phosphoadenosine phosphosulfate (PAPS) as substrate and catalyze reactions (shown in Figure 2-36).

The glucuronyl transferases that are localized in the liver endoplasmic reticulum use uridine-diphosphoglucuronic acid (UDPGA) as a substrate and catalyze the following reaction:

References

A. Books

Dorfman, R. I., and Ungar, F. (1965). "Metabolism of Steroid Hormones." Academic Press, New York. Fieser, L., and Fieser, M. (1959). "Steroids." Van Nostrand-Reinhold, Princeton, NJ.

Makin, H. L. (1975). "Biochemistry of Steroid Hormones." Blackwell, Oxford, UK.

B. Review Articles

Barton, D. H. R., and Cookson, R. C. (1956). Steroid conformational analysis. Q. Rev. Chem. Soc. 10, 44-53.

Bloch, K. (1965). The biological synthesis of cholesterol. Science 150, 19-23.

Brown, M. S., and Goldstein, J. L. (1976). Receptor-mediated control of cholesterol metabolism. Science 191, 150-154.

IUPAC Rules of Steroid Nomenclature (1972). Pure Appl. Chem. 31, 285-322.

Miller, W. L. (1988). Molecular biology of steroid hormone synthesis. Endocrine Rev. 9, 295-318.

Nebert, D. W., Adesnik, M., Coon, M. J., Estabrook, R. W., Gonzales, J., Guengerich, F. P., Gunsalus, I. C., Johnson, E. F., Kemper, B., Levin, W., Phillips, I. R., Sato, R., and Waterman, M. R. (1987). The P450 gene superfamily: Recommended nomenclature. DNA Cell Biol. 6, 1-51.

Popjak, G., and Cornforth, J. W. (1960). The biosynthesis of cholesterol. Adv. Enzymol. 22, 281-335.

Rosner, W. (1990). The functions of corticosteroid-binding globulin and sex hormone-binding globulin: Recent advances. Endocrine Rev. 11, 80-91.

Simpson, E. R., Mahendroo, M. S., Means, G. D., Kilgore, M. W., Hinshelwood, M. M., Graham-Lorenc, S., Amarneh, B., Ito, Y., Fisher, C. R., Michael, M. D., Mendelson, C. R., and Bulun, S. E. (1994). Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocrine Rev. 15, 342-355.

Tait, J. F. (1963). The use of isotopic steroids for the measurement of production rates in vivo. 1. Clin. Endocrinol. Metab. 23,1285-1297.

Tait, J. F., and Horton, R. (1966). Steroid compartmental analysis. In "Steroid Dynamics" (G. Pincus, J. F. Tait, and T. Nakao, eds.), p. 393. Academic Press, New York.

White, P. C., Curnow, K. M., and Pascoe, L. (1994). Disorders of steroid 11/3-hydroxylase isoenzymes. Endocrine Rev. 15,421-438.

C. Research Papers

Bearer, E., and Orci, L. (1985). Endothelial fenestral diaphragms: A quick-freeze, deep etch study. ]. Cell Biol. 100, 418-428.

Black, S. M., Harikrishna, J. A., Szklarz, G. D„ and Miller, W. L. (1994). The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc. Proc. Natl. Acad. Sci. USA 91, 7247-7251.

Black, S. M., Szklarz, G. D., Harikrishna, J. A., Lin, D., Wolf, R„ and Miller, W. L. (1993). Regulation of proteins in the cholesterol side-chain cleavage system in JEG-3 and Y-l cells. Endocrinology 132, 539-545.

Cahn, R. S., Ingold, C. K., and Prelog, V. (1966). Specification of molecular chirality. Angew. Chem., Int. Ed. Engl. 5,385-415. (This paper describes the "sequence rule" for determination of R vs S asymmetry.)

Clark, B. J., Wells, J., King, S. R., and Stocco, D. M. (1994). The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Ley dig tumor cells, characterization of the steroidogenic acute regulatory protein (StAR). J. Biol. Chem. 269, 28314-28322.

Honda, S., Morohashi, K., Nomura, M., Takeya, H., Kitajima, M., and Omura, T. (1993). Ad4BP regulating steroidogenic P-450 gene is a member of steroid hormone receptor superfamily. J. Biol. Chem. 268, 7494-7502.

Lin, D., Sugawara, T., Strauss, J. R, III, Clark, B. J., Stocco, D. M., Saenger, P., Rogol, A., and Miller, W. L. (1995). Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science 267, 1828-1830.

Nomura, M., Morohashi, K., Kirita, S., Nonaka, Y., Okamoto, M., Nawata, H., and Omura, T. (1993). Three forms of rat CYP11B genes: 11/3-Hydroxylase gene, aldosterone synthase gene, and a novel gene. J. Biochem. (Tokyo) 113, 144-152.

Van Tamelen, E. E., Leopold, E. J., Marason, S. A., and Walspe, H. R. (1982). Action of 2,3-oxidosqualene-lanosterol cyclase on 15-nor-18,19-dihydro-2,3-oxidosqualene. J. Am. Chem. Soc. 104, 6479-6480.

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